SYNERGISTIC GROWTH INHIBITORY EFFECT OF FLAVONOL–KAEMPFEROL AND CONVENTIONAL CHEMOTHERAPEUTIC DRUGS ON CANCER CELLS

摘要

Objective: The objective of the present study was to evaluate synergistic growth inhibitory effect of a flavonol, kaempferol in combination with chemotherapeutic drugs doxorubicin or cisplatin. Methods: The anti-proliferative activities of kaempferol, doxorubicin and cisplatin on human colorectal cancer cells (HCT-15) and human breast cancer (MDA MB 231) were analyzed by 3-(4,5-dimehylthiaol-2-yl)-2,5-diphenyltetraolium bromide (MTT) assay. Further, combinational studies were performed in both the cell lines to evaluate the interaction of drugs with kaempferol. The combination index (CI) method was used to assess the synergism of kaempferol with doxorubicin or cisplatin. Finally, morphological alterations associated with apoptosis were examined under fluorescent microscope. Results: All compounds showed dose-dependent growth inhibition in both HCT-15 and MDA MB 231 cells. The phytochemical kaempferol showed fifty percent inhibitory concentrations (IC 50 ) at 120±3.2 μg/ml and 64±1.2 μg/ml on HCT-15 and MDA MB 231 respectively. IC 50 concentrations of doxorubicin and cisplatin on both the cell lines were achieved at 49.6±0.5 μg/ml, 25.4±2.9 μg/ml and 44±1.8 μg/ml, 40.6±0.8 μg/ml respectively. Further, in vitro therapeutic effect (IC 50 ) of doxorubicin and cisplatin in terms of cell growth inhibition on HCT-15 cells were achieved at their one-fifth (10±0.83 μg/ml) and half (10±1.34 μg/ml) concentrations respectively when they were combined with 30 μg/ml of kaempferol individually. Simultaneously, on MDA-MB 231 cell line, the IC 50 concentrations were reduced to 18±1.22 μg/ml and 15±1.87 μg/ml respectively in combination with 32 μg/ml of kaempferol. The combinational index studies revealed the synergistic association of kaempferol with doxorubicin and cisplatin individually in each cell line. The fluorescence imaging studies strongly supported the synergistic association between kaempferol and doxorubicin or cisplatin by confirming significant apoptotic cell death in both the cell lines which was ~3 fold higher than each agent alone. Conclusion: The study reveals the prominent synergism between the phytochemical, kaempferol and chemotherapeutic drugs doxorubicin or cisplatin which helps in elevating the therapeutic efficacy of drugs.